Project Summary/Abstract The understanding of normal cognitive function and the development of treatments for neurodegenerative diseases have been enabled by the study of natural products and their synthetic congeners. The extensive discoveries made in this realm have been limited primarily to the specific activities of abundantly available natural products or simple derivatives thereof. The long-term goal of this proposal is to use fragment-coupling approaches to synthesize varied, stereochemically rich, polycyclic natural product architectures with the potential to further the understanding of neurodegenerative disorders. This proposal outlines two convergent approaches for the synthesis of two families of natural products, the grayanotoxins and the limonoids, both of which have been shown to attenuate neuronal cell death caused by reactive oxygen species. By departing from conventional strategies that cyclize linear precursors, this proposal utilizes the convergent and scalable assembly of building blocks into structurally differentiated scaffolds. In line with conventional approaches, the molecular architectures obtained through this approach will be subsequently modified through the application of a dehydrogenation methodology recently reported by our laboratory, as well as by other chemical strategies. Novel analogs produced by these routes will be evaluated for their ability to alleviate the effects of reactive oxygen species on neurodegeneration. Through increased understanding of neurodegeneration on a molecular level, potential avenues for drug discovery and therapeutic intervention will be revealed.